Polycythemia Vera and Essential Thrombocythemia Lorenzo Falchi, MD, and Srdan Verstovsek, MD, Phd

Clinical Review

Polycythemia Vera and Essential Thrombocythemia Lorenzo Falchi, MD, and Srdan Verstovsek, MD, PhD

poietic stem cell, but are characterized by distinct clinical ABSTRACT phenotypes [1,2]. Although the clinical course of PV and Objective: To review the clinical aspects and current ET is indolent, it can be complicated by thrombohemor- practices in the management of polycythemia vera (PV) rhagic episodes and/or evolution into myelofibrosis and/or and essential thrombocythemia (ET). acute myeloid leukemia (AML) [3]. Since vascular events Methods: Review of the literature. are the most frequent life-threatening complications of PV Results: PV and ET are rare chronic myeloid disorders. The and ET, therapeutic strategies are aimed at reducing this 2 most important life-limiting complications of PV and risk. Treatment may also help control other symptoms as- ET are thrombohemorrhagic events and myelofibrosis/ sociated with the disease [4]. No therapy has been shown acute myeloid leukemia (AML) transformation. to prevent evolution of PV or ET into myelofibrosis or AML. Vascular events are at least in part preventable with The discovery of the Janus kinase 2 (JAK2)/V617F muta- counseling on risk factors, phlebotomy (for patients tion in most patients with PV and over half of those with with PV), antiplatelet therapy, and cytoreduction with ET (and PMF) [5,6] has opened new avenues of research hydroxyurea, interferons, or anagrelide (for patients and led to the development of targeted therapies, such as with ET). Ruxolitinib was recently approved for PV the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8]. after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history Epidemiology of the disease and no therapy has been shown to PV and ET are typically diagnosed in the fifth to seventh prevent it. Treatment of leukemic transformation decade of life [9]. Although these disorders are generally of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis associated with a long clinical course, survival of patients and AML. with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near- of MPN is a challenge because most patients remain normal quality of life. Transformation into myelofibrosis asymptomatic for long periods of time and do not seek or AML cannot be prevented by current therapies, medical attention [13]. The annual incidence rates of PV however. Treatment results with MPN LT are generally and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per poor and novel strategies are needed to improve 100,000, respectively. PV occurs slightly more frequently outcomes. in males, whereas ET has a predilection for females [14]. Key words: myeloproliferative neoplasms; myelofibrosis; Given the long course and low mortality associated with leukemic transformation. these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17]. olycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative my- P From the Columbia University Medical Center, New York, NY (Dr. eloproliferative neoplasms (MPN). All these malignancies Falchi), and the University of Texas MD Anderson Cancer Center, arise from the clonal proliferation of an aberrant hemato- Houston, TX (Dr. Verstovsek).

www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 371 Polycythemia Vera and Essential Thrombocythemia

Molecular Pathogenesis tomatic than ET and can present with debilitating consti- In 2005 researchers discovered a gain-of-function mu- tutional symptoms (fatigue, night sweats, and weight loss), tation of the JAK2 gene in nearly all patients with PV and microvascular symptoms (headache, lightheadedness, more than half of those with ET and PMF [5,6,18,19]. JAK2 acral paresthesias, erythromelalgia, atypical chest pain, is a non-receptor tyrosine kinase that plays a central role in and pruritus) [31], or macrovascular accidents (larger vein normal hematopoiesis. Substitution of a valine for a phe- thrombosis, stroke, or myocardial ischemia) [32]. ET is nylalanine at codon 617 (ie, V617F) leads to its constitutive often diagnosed incidentally, but patients can suffer from activation and signaling through the JAK-STAT pathway similar general symptoms and vascular complications. [5,6,18,19]. More rarely (and exclusively in patients with Causes of secondary absolute erythrocytosis (altitude, PV), JAK2 mutations involve exon 12 [20–22]. The vast chronic hypoxemia, heavy smoking, cardiomyopathy, use majority of JAK2-negative ET patients harbor mutations in of corticosteroids, erythropoietin, or other anabolic hor- either the myeloproliferative leukemia (MPL) gene, which mones, familial or congenital forms) or thrombocytosis encodes the thrombopoietin receptor [23–25], or the cal- (iron deficiency, acute blood loss, trauma or injury, acute reticulin (CALR) gene [26,27], which encodes for a chap- coronary syndrome, systemic autoimmune disorders, erone protein that plays a role in cellular proliferation, dif- chronic kidney failure, other malignancies, splenectomy) ferentiation, and apoptosis [28]. Both the MPL and CALR should be considered and appropriately excluded. Once mutations ultimately result in the constitutive activation the diagnosis is made, symptom assessment tools such of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR as the Myeloproliferative Neoplasm Symptom Assess- alterations are collectively referred to as driver mutations. ment Form (MPN-SAF) [33] or the abbreviated version, Moreover, because these mutations affect the same on- the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], cogenic pathway (ie, JAK-STAT), they are almost always are generally used to assess patients’ symptom burden mutually exclusive in a given patient. Patients with ET and response to treatment in everyday practice. (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Risk Stratification Many recurrent non-driver mutations are also found in pa- Thrombohemorrhagic events, evolution into myelofibro- tients with MPN. These are not exclusive of each other sis, and leukemic transformation (LT) are the most serious (ie, patients may have many at the same time) and involve complications in the course of PV or ET. Only thrombo- for example ten-eleven translocation-2 (TET2), addition- hemorrhagic events are, at least partially, preventable. Ar- al sex combs like 1 (ASXL1), enhancer of zeste homolog terial or venous thrombotic complications are observed 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate de- at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial hydrogenase 2 (IDH1/2), and DNA methyltransferase 3A thrombosis being more common than venous) and 0.74 (DNMT3A) genes, among others [29]. The biologic and to 7.7 per 100 patient-years in ET, depending on the risk prognostic significance of these non-driver alterations re- group [35] and the presence of other factors (see below). main to be fully defined in ET and PV. The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. Diagnostic Criteria If either is present, the patient is assigned to the high- Diagnostic criteria for PV and ET according to the World risk category, whereas if none is present the patient is Health Organization (WHO) classification [30] are sum- considered at low risk [36]. In addition, high hematocrit marized in Table 1. Criteria for the diagnosis of prefibrotic [37] and high white blood cell (WBC) count [38], but myelofibrosis are included as well since this entity was not thrombocytosis, have been associated with the formally recognized as separate from ET and part of the development of vascular complications. In one study, PMF spectrum in the 2016 WHO classification of myeloid the risk of new arterial thrombosis was increased by the tumors [30]. Clinically, both PV and ET generally remain presence of leukoerythroblastosis, hypertension, and asymptomatic for a long time. PV tends to be more symp- prior arterial thrombosis, while karyotypic abnormalities

372 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal Clinical Review

Table 1. World Health Organization Diagnostic Criteria for Polycythemia Vera, Essential Thrombocythemia, and Prefibrotic Myelofibrosis

Polycythemia Vera Essential Thrombocythemia Prefibrotic Myelofibrosis

Major criteria 1. Hemoglobin > 16.5 g/dL (men) 1. Elevated platelet count (ie, ≥ 450 x 1. Megakaryocytic proliferation or 16.0 g/dL (women) or hematocrit 103/μL) and atypia, without reticulin > 49% (men) or 48% (women), or fibrosis > grade 1, accompanied increased red cell mass 2. Bone marrow showing proliferation, by increased age-adjusted bone mainly of the megakaryocyte marrow cellularity, granulocytic 2. Bone marrow hypercellular for lineage, without increase or left proliferation, and often decreased age with trilineage growth including shift in neutrophil granulopoiesis or erythropoiesis pleomorphic, mature megakaryocytes erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers 2. Does not meet WHO criteria 3. Presence of the JAK2V617F or for BCR-ABL1+ CML, PV, ET, JAK2 exon 12 mutation 3. Lack of diagnostic criteria for any myelodysplastic syndromes, or other myeloid neoplasm other myeloid neoplasms 4. Presence of clonal markers, such as 3. Presence of JAK2, CALR, or the JAK2, CALR, or MPL mutations MPL mutation or in the absence of these mutations, presence of another clonal marker,* or absence of minor reactive bone marrow reticulin fibrosis†

Minor criteria Subnormal serum erythropoietin level Presence of a clonal marker or Presence confirmed in 2 exclusion of reactive thrombocytosis consecutive determinations of: a. Anemia not attributed to comorbid conditions b. Leukocytosis ≥ 11,000/μL c. Palpable splenomegaly d. LDH increased above the upper limit of institutional reference range

Diagnosis 3 major criteria or 2 major criteria + 4 major criteria or the first 3 major 3 major criteria and at least 1 minor criterion criteria + minor criterion minor criterion

Adapted from Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391–405. CML, chronic myeloid leukemia; ET, essential thrombocythemia; LDH, lactate dehydrogenase; PV, polycythemia vera. *Either a driver mutation or another recurrent mutation (eg, ASXL1, EXH2, TET2, IDH1/2, SRSF2, SF3B1). †Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.

and prior venous thrombosis were predictors of new of new relevant factors. In particular, the impact of JAK2 venous thrombosis [39]. Another emerging risk factor for mutations on thrombotic risk has been thoroughly stud- thrombosis in patients with PV is high JAK2 allele burden ied. Clinically, the presence of JAK2V617F is associated (ie, the normal-to-mutated gene product ratio), although with older age, higher hemoglobin and hematocrit, lower the evidence supporting this conclusion is equivocal [40]. platelet counts, more frequent need for cytoreductive Traditionally, in ET patients, the thrombotic risk was treatment, and greater tendency to evolve into PV (a rare assessed using the same 2 factors (age ≥ 60 years and event) [41,42]. Many [41,43–46], but not all [47–51], studies prior history of thrombosis), separating patients into low- suggested a correlation between JAK2 mutation and risk and high-risk groups. However, the prognostication of ET of both arterial and venous thrombosis. Although infre- patients has been refined recently with the identification quent, a JAK2V617F homozygous state (ie, the mutation is www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 373 Polycythemia Vera and Essential Thrombocythemia

Table 2. Revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis)

Risk factors Age > 60 yr Prior thrombosis JAK2V617F mutation

Risk groups Very low-risk: no prior thrombosis, age ≤ 60 yr, wild-type JAK2 Low-risk: no prior thrombosis, age ≤ 60 yr, JAK2-mutated Intermediate-risk: no prior thrombosis, age > 60 yr, wild-type JAK2 High-risk: prior thrombosis or age > 60 yr and JAK2-mutated

Adapted from Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 2015;5:e369.

present in both alleles) might confer an even higher throm- ported for ET patients with JAK2V617F mutations [73]. The botic risk [52]. Moreover, the impact of the JAK2 mutation presence of the mutation per se does not appear to affect on vascular events persists over time [53], particularly in the thrombotic risk [74–76]. Information on the thrombotic patients with high or unstable mutation burden [54]. Based risk associated with MPL mutations or a triple-negative on JAK2V617F’s influence on the thrombotic risk of ET state is scarce. In both instances, however, the risk appears patients, a new prognostic score was proposed, the In- to be lower than with the JAK2 mutation [73,77–79]. ternational Prognostic Score for ET (IPSET)-thrombosis Venous thromboembolism (VTE) in patients with PV (Table 2). The revised version of this model is currently en- or ET may occur at unusual sites, such as the splanchnic dorsed by the National Comprehensive Cancer Network or cerebral venous systems [80]. Risk factors for unusual and divides patients into 4 risk groups: high, intermediate, VTE include younger age [81], female gender (especially low, and very low. Treatment recommendations vary ac- with concomitant use of oral contraceptive pills) [82], cording to the risk group (as described below) [55]. and splenomegaly/splenectomy [83]. JAK2 mutation has Other thrombotic risk factors have been identified, also been associated with thrombosis at unusual sites. but deemed not significant enough to be included in the However, the prevalence of MPN or JAK2V617F in pa- model. Cardiovascular risk factors (hypercholesterolemia, tients presenting with splanchnic VTE has varied [80]. In hypertension, smoking, diabetes mellitus) can increase the addition, MPN may be occult (ie, no clinical or laboratory risk of vascular events [56–59], as can splenomegaly [60] abnormalities) in around 15% of patients [84]. Screening and baseline or persistent leukocytosis [61–63]. Thrombo- for JAK2V617F and underlying MPN is recommended in cytosis has been correlated with thrombotic risk in some patients presenting with isolated unexplained splanchnic studies [64–68], whereas others did not support this con- VTE. Treatment entails long-term anticoagulation therapy. clusion and/or suggested a lower rate of thrombosis and, JAK2V617F screening in patients with nonsplanchnic VTE in some cases, increased risk of bleeding in ET patients is not recommended, as its prevalence in this group is low with platelet counts greater than 1000 × 103/μL (due to (< 3%) [85,86]. acquired von Willebrand syndrome) [51,61,63,68,69]. CALR mutations tend to occur in younger males with Risk-Adapted Therapy lower hemoglobin and WBC count, higher platelet count, Low-Risk PV and greater marrow megakaryocytic predominance, as All patients with PV should receive counseling to mitigate compared to JAK2 mutations [26,27,70–72]. The associated cardiovascular risk factors, including smoking cessation, incidence of thrombosis was less than 10% at 15 years in lifestyle modifications, and lipid-lowering therapy, as indi- patients with CALR mutations, lower than the incidence re- cated. Furthermore, all PV patients should receive acetyl-

374 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal Clinical Review

salicylic acid (ASA) to decrease their risk for thrombosis IFN-alfa is a pleiotropic antitumor agent that has found and control vasomotor symptoms [55,87]. Aspirin 81 to 100 application in many types of malignancies [96] and is mg daily is the preferred regimen because it provides ade- sometimes employed as treatment for patients with newly quate antithrombotic effect without the associated bleed- diagnosed high-risk PV. Early studies showed responses ing risk of higher-dose aspirin [88]. Low-risk PV patients in up to 100% of cases [97,98], albeit at the expense of a should also receive periodic phlebotomies to reduce and high discontinuation rate due to adverse events, such as maintain their hematocrit below 45%. This recommenda- flu-like symptoms, fatigue, and neuropsychiatric manifes- tion is based on the results of the Cytoreductive Therapy tations [99]. A newer formulation of the drug obtained by in Polycythemia Vera (CYTO PV) randomized controlled adding a polyethylene glycol (PEG) moiety to the native trial. In that study, patients receiving more intense therapy IFN-alfa molecule (PEG-IFN alfa) was shown to have a to maintain the hematocrit below 45% had a lower inci- longer half-life, greater stability, less immunogenicity, dence of cardiovascular-related deaths or major throm- and, potentially, better tolerability [100]. Pilot phase 2 botic events than those with hematocrit goals of 45% to trials of PEG-IFN-alfa-2a demonstrated its remarkable 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option activity, with symptomatic and hematologic responses for low-risk patients who do not tolerate phlebotomy or re- seen in most patients (which, in some cases, persisted quire frequent phlebotomy, or who have disease-related beyond discontinuation), and reasonable tolerability, with bleeding, severe symptoms, symptomatic splenomegaly, long-term discontinuation rates of 20% to 30% [101–103]. or progressive leukocytosis [38]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 High-Risk PV (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET Patients older than 60 years and/or with a history of [NCT01259817]) and MPD-RC112 (randomized controlled thrombosis should be considered for cytoreductive trial, PEG-IFN-alfa-2a versus hydroxyurea in the same therapy in addition to the above measures. Frontline cy- population [NCT01258856]), will shed light on the role of toreductive therapies include hydroxyurea or interferon PEG-IFN-alfa in the management of patients with high- (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide re- risk PV or ET. In two phase 2 studies of PEG-IFN-alfa- ductase inhibitor that interferes with DNA repair and is 2b, complete responses were seen in 70% to 100% of the treatment of choice for most high-risk patients with patients and discontinuation occurred in around a third PV [90]. In a small trial, hydroxyurea reduced the risk of of cases [105,106]. A new, longer-acting formulation of thrombosis compared with historical controls treated PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is with phlebotomy alone [91]. Hydroxyurea is generally well also undergoing clinical development [107,108]. tolerated; common side effects include cytopenias, nail The approach to treatment of PV based on thrombotic changes, and mucosal and/or skin ulcers. Although never risk level is illustrated in Figure 1. formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the Very Low- and Low-Risk ET original study, the rates of transformation were 5.9% and Individuals with ET should undergo rigorous cardiovas- 1.5% for patients receiving hydroxyurea and phlebotomy cular risk management and generally receive ASA to de- alone [92], respectively, although an independent role for crease their thrombotic risk and improve symptom con- hydroxyurea in LT was not supported in the much larger trol. Antiplatelet therapy may not be warranted in patients European Collaboration on Low-dose Aspirin in Polycy- with documented acquired von Willebrand syndrome, themia Vera (ECLAP) study [93]. Approximately 70% of with or without extreme thrombocytosis, or in those in the patients will have a sustained response to hydroxyurea very low-risk category according to the IPSET-thrombosis [94], while the remaining patients become resistant to or model [55,87]. The risk/benefit ratio of antiplatelet agents intolerant of the drug. Resistant individuals have a higher in patients with ET at different thrombotic risk levels was risk of progression to acute leukemia and death [95]. assessed in poor-quality studies and thus remains highly www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 375 Polycythemia Vera and Essential Thrombocythemia

Diagnosis of PV

Risk stratification

Low risk High risk

• Clinical monitoring for • Clinical monitoring for thrombosis or bleeding thrombotic events • Cardiovascular risk reduction • Cardiovascular risk reduction • Low-dose aspirin • Low-dose aspirin • Phlebotomy (Ht goal < 45%)

Assess need for cytoreduction every 3–6 months

No Cytoreductive therapy Indications for Yes cytoreductive therapy?* • Hydroxyurea • Interferons

Monitor every 3–6 months

No Loss of response* *Any of the following: or intolerance • New thrombosis Yes • Frequent/persistent phlebotomy • Symptomatic/progressive splenomegaly Change therapy • Symptomatic thrombocytosis • Ruxolitinib • Progressive leukocytosis • Hydroxyurea (if not previously used) • Disease-related symptoms • Interferons (if not previously used)

Evolution into MF or AML  treat accordingly

Figure 1. Polycythemia vera (PV) treatment algorithm. AML, acute myeloid leukemia; MF, myelofibrosis. uncertain. Platelet-lowering agents are sometimes rec- symptoms despite ASA, symptomatic or progressive ommended in patients with low-risk disease who have splenomegaly, and progressive leukocytosis. platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleed- Intermediate-Risk ET ing (this would require stopping ASA) [109]. Cytoreduction This category includes patients older than 60 years, but may also be used in low-risk patients with progressive without thrombosis or JAK2 mutations. These individuals

376 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal Clinical Review

would have been considered high risk (and thus candi- responses observed in 80% of patients [103]. PEG-IFN- dates for cytoreductive therapy) according to the tradi- alfa-2b produced similar results, with responses in 70% tional risk stratification. Guidelines currently recommend to 90% of patients in small studies and discontinuation ASA as the sole therapy for these patients, while reserv- observed in 20% to 38% of cases [105,106,113]. Because ing cytoreduction for those who experience thrombosis the very long-term leukemogenic potential of hydroxyurea (ie, become high-risk) or have uncontrolled vasomotor or has remained somewhat uncertain, anagrelide or IFN general symptoms, symptomatic splenomegaly, symp- might be preferable choices in younger patients. tomatic thrombocytosis, or progressive leukocytosis. The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2. High-Risk ET For patients with ET in need of cytoreductive therapy (ie, Assessing Response to Therapy those with prior thrombosis or older than 60 years with a For both patients with PV and ET the endpoint of treat- JAK2V617F mutation), first-line options include hydroxy- ment set forth for clinical trials has been the achievement urea, IFN, and anagrelide. Hydroxyurea remains the treat- of a clinicohematologic response. However, studies have ment of choice in most patients [110]. In a seminal study, failed to show a correlation between response and re- 114 patients with ET were randomly assigned to either ob- duction of the thrombohemorrhagic risk [114]. Therefore, servation or hydroxyurea treatment with the goal of main- proposed clinical trial response criteria were revised to taining the platelet count below 600 × 103/μL. At a median include absence of hemorrhagic or thrombotic events as follow-up of 27 months, patients in the hydroxyurea group part of the definition of response (Table 3) [94]. had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use Approach to Patients Refractory to or of antiplatelet drugs [64]. Intolerant of First-line Therapy Anagrelide, a selective inhibitor of megakaryocytic According to the European LeukemiaNet recommenda- differentiation and proliferation, was compared with hy- tions, an inadequate response to hydroxyurea in patients droxyurea in patients with ET in 2 randomized trials. In with PV (or myelofibrosis) is defined as a need for phlebot- the first (n = 809), the group receiving anagrelide had a omy to maintain the hematocrit below < 45%, the platelet higher risk of arterial thrombosis, major bleeding, and count > 400 × 103/μL, and a WBC count > 10,000/μL, or fibrotic evolution, but lower incidence of venous throm- failure to reduce splenomegaly > 10 cm by > 50% at a dose bosis. Hydroxyurea was better tolerated, mainly due to of ≥ 2 g/day or maximum tolerated dose. Historically, treat- anagrelide-related cardiovascular adverse events [111]. ment options for patients with PV or ET who failed first-line As a result of this study, hydroxyurea is often preferred therapy (most commonly hydroxyurea) have included al- to anagrelide as frontline therapy for patients with newly kylating agents, such as busulfan, chlorambucil, pipobro- diagnosed high-risk ET. In the second, more recent study man, and phosphorus (P)-32. However, the use of these (n = 259), however, the 2 agents proved equivalent in drugs is limited by the associated risk of LT [93,115,116]. terms of major or minor arterial or venous thrombosis, IFN (or anagrelide for ET) is often considered in patients as well as discontinuation rate [112]. The discrepancy be- previously treated with hydroxyurea, and vice versa. tween the 2 trials may be partly explained by the different Ruxolitinib is a JAK1 and JAK2 inhibitor currently ET diagnostic criteria used, with the latter only enrolling approved for the treatment of PV patients refractory to patients with WHO-defined true ET and the former uti- or intolerant of hydroxyurea [7]. Following promising re- lizing Polycythemia Vera Study Group-ET diagnostic cri- sults of a phase 2 trial [117], ruxolitinib 10 mg twice daily teria that included patients with increases in other blood was compared with best available therapy in the pivotal counts or varying degrees of marrow fibrosis. RESPONSE trial (n = 222). Ruxolitinib proved superior in Interferons were studied in ET in parallel with PV. achieving hematocrit control, reduction of spleen volume, PEG-IFN-alfa-2a proved effective in patients with ET, with and improvement of symptoms. Grade 3-4 hematologic www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 377 Polycythemia Vera and Essential Thrombocythemia

Diagnosis of ET

Risk stratification (revised IPSET-thrombosis)

Very low risk Low risk Intermediate risk High risk

• Clinical monitoring for • Clinical monitoring for • Clinical monitoring for • Clinical monitoring for thrombosis or bleeding thrombosis or bleeding thrombosis or bleeding thrombosis or bleeding • Cardiovascular risk • Cardiovascular risk • Cardiovascular risk • Cardiovascular risk reduction reduction reduction reduction • Low-dose aspirin or • Low-dose aspirin • Low-dose aspirin • Low-dose aspirin observation

+ Assess need for cytoreduction every 3–6 months

Cytoreductive therapy No Indications for Yes • Hydroxyurea cytoreductive therapy?* • Anagrelide • Interferons

Monitor every 3–6 months

No Loss of response* or intolerance *Any of the following: Yes • New thrombosis • Acquired von Willebrand syndrome Change therapy • Symptomatic/progressive splenomegaly • Hydroxyurea (if not previously used) • Progressive leukocytosis • Anagrelide (if not previously used) • Disease-related symptoms • Interferons (if not previously used)

Evolution into MF or AML  treat accordingly

Figure 2. Essential thrombocythemia (ET) treatment algorithm. AML, acute myeloid leukemia; MF, myelofibrosis. toxicity was infrequent and similar in the 2 arms [118]. patients in the ruxolitinib arm had hematocrit reduction In addition, longer follow-up of that study suggested without an increase in toxicity. Based on the results of a lower rate of thrombotic events in patients receiving these studies, ruxolitinib can be considered a standard ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In of care for second-line therapy in this post-hydroxyurea a similarly designed randomized phase 3 study in PV patient population [120]. Ruxolitinib is also being tested patients without splenomegaly (RESPONSE-2), more in patients with high-risk ET who have become resistant

378 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal Clinical Review

Table 3. ELN and IWG-MNRT Treatment Response Criteria (2013)

Type of Response Essential Thrombocythemia Polycythemia Vera

Complete remission Resolution of disease-related signs, including Resolution of disease-related signs, including palpable hepatosplenomegaly for ≥ 12 wk, ≥ 10- palpable hepatosplenomegaly for ≥ 12 wk, ≥ 10- point decrease in the MPN-SAF TSS, plus point decrease in the MPN-SAF TSS, plus Durable peripheral blood count remission defined Durable peripheral blood count remission defined as: platelet count ≤ 400 x 103/μL, WBC count < as: hematocrit < 45%, platelet count ≤ 400 x 10,000/μL, absence of leukoerythroblastosis, plus 103/μL, WBC count < 10,000/μL, absence of leukoerythroblastosis, plus No signs of progressive disease, and absence of any hemorrhagic or thrombotic events plus No signs of progressive disease, and absence of any hemorrhagic or thrombotic events plus Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia and Bone marrow histological remission defined as absence of > grade 1 reticulin fibrosis the presence of age-adjusted normocellularity and disappearance of trilineage hyperplasia, and absence of > grade 1 reticulin fibrosis

Partial remission Resolution of disease-related signs, including Resolution of disease-related signs, including palpable hepatosplenomegaly for ≥ 12 wk, palpable hepatosplenomegaly for ≥ 12 wk, ≥ 10-point decrease in the MPN-SAF TSS, plus ≥ 10-point decrease in the MPN-SAF TSS, plus Durable peripheral blood count remission defined Durable peripheral blood count remission defined as: platelet count ≤ 400 x 103/μL, WBC count < as: hematocrit < 45%, platelet count ≤ 400 x 10,000/μL, absence of leukoerythroblastosis, plus 103/μL, WBC count < 10,000/μL , absence of leukoerythroblastosis, plus No signs of progressive disease, and absence of any hemorrhagic or thrombotic events plus No signs of progressive disease, and absence of any hemorrhagic or thrombotic events plus Without bone marrow histological remission, defined as the persistence of megakaryocyte Without bone marrow histological remission, hyperplasia defined as persistence of trilineage hyperplasia

No response Any response that does not fit partial remission Any response that does not fit partial remission

Progressive disease Transformation into PV, post-ET myelofibrosis,* or Transformation into post-ET myelofibrosis,* MDS, MDS/acute leukemia [30] or acute leukemia [30]

Adapted from et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood 2013;121:4778–81. ELN, European LeukemiaNet; ET, essential thrombocythemia; IWG-MNRT, International Working Group–Myeloproliferative Neoplasms Research and Treatment; MPN-SAF TSS, Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score; PV, polycythemia vera. *Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 2008;22:437–8.

to, or were intolerant of hydroxyurea, but currently has Disease Evolution no approved indication in this setting [121,122]. Common Post-PV/Post-ET Myelofibrosis side effects of ruxolitinib include cytopenias (especially Diagnostic criteria for post-PV and post-ET myelofibro- anemia), increased risk of infections, hyperlipidemia, and sis are outlined in Table 4. Fibrotic transformation rep- increased risk of non-melanoma skin cancer. resents a natural evolution of the clinical course of PV Novel agents that have been studied in patients with or ET. It occurs in up to 15% and 9% of patients with PV and ET are histone deacetylase inhibitors, murine PV and ET, respectively, in western countries [124]. The double minute 2 (MDM2, or HDM2 for their human true percentage of ET patients who develop myelofibro- counterpart) inhibitors (which restore the function of p53), sis is confounded by the inclusion of prefibrotic myelo- Bcl-2 homology domain 3 mimetics such as navitoclax fibrosis cases in earlier series. The survival of patients and venetoclax, and, for patients with ET, the telomerase who develop myelofibrosis is shortened compared to inhibitor imetelstat [123]. those who do not. In patients with PV, risk factors for www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 379 Polycythemia Vera and Essential Thrombocythemia

Table 4. Diagnostic Criteria for Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis

Post-PV MF Post-ET MF

Required criteria Documentation of preexisting WHO-defined PV Documentation of preexisting WHO-defined ET Bone marrow fibrosis grade 2 or 3 (on the Bone marrow fibrosis grade 2 or 3 (on the European 0–3 scale) or grade 3 or 4 (on the European 0–3 scale) or grade 3 or 4 (on the standard 0–4 scale) standard 0–4 scale)

Additional criteria (at least 2) Anemia or sustained loss of requirement for Anemia and a 2 g/dL loss in hemoglobin phlebotomy (without cytoreductive therapy) from baseline or cytoreductive treatment for erythrocytosis Peripheral blood leukoerythroblastosis Peripheral blood leukoerythroblastosis Splenomegaly ≥ 5 cm below the costal margin Splenomegaly ≥ 5 cm below the costal margin or new palpable splenomegaly or new palpable splenomegaly At least 1 of: ≥ 10% weight loss, night sweats, At least 1 of: ≥ 10% weight loss, night sweats, unexplained fever > 37.5°C unexplained fever > 37.5°C

Adapted from Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 2008;22:437–8. ET, essential thrombocythemia; MF, myelofibrosis; PV, polycythemia vera; WHO, World Health Organization.

myelofibrosis evolution include advanced age, leukocy- agents or P-32, splenectomy, increased peripheral blood tosis, JAK2V617F homozygosity or higher allele burden, or bone marrow blasts, leukocytosis, anemia, thrombo- and hydroxyurea therapy. Once post-PV myelofibrosis cytopenia, and cytogenetic abnormalities. Hydroxyurea, has occurred, hemoglobin < 10 g/dL, platelet count IFN, and ruxolitinib have not been shown to have leuke- < 100 × 103/μL, and WBC count > 30,000/μL are asso- mogenic potential thus far. Prognosis of LT is uniformly ciated with worse outcomes [125]. In patients with ET, poor and patient survival rarely exceeds 6 months. risk factors for myelofibrosis transformation include age, There is no standard of care for MPN LT. Treatment anemia, bone marrow hypercellularity and increased re- options range from low-intensity regimens to more ag- ticulin, increased lactate dehydrogenase, leukocytosis, gressive AML-type induction chemotherapy. No strategy and male gender. The management of post-PV/post-ET appears clearly superior to others [128]. Hematopoietic myelofibrosis recapitulates that of PMF. stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is ap- Leukemic Transformation plicable only to a minority of patients with chemosensitive The presence of more than 20% blasts in peripheral blood disease and good performance status [130]. Notable or bone marrow in a patient with MPN defines LT. This experimental approaches to MPN LT include hypometh- occurs in up to 5% to 10% of patients and may or may ylating agents, such as decitabine [131] or azacytidine not be preceded by a myelofibrosis phase [126]. In cases [132], with or without ruxolitinib [133–135]. of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the Conclusion peripheral blood. The pathogenesis of LT has remained PV and ET are rare, chronic myeloid disorders. Patients elusive, but it is believed to be associated with genetic in- typically experience a long clinical course and enjoy stability, which facilitates the acquisition of additional mu- near-normal quality of life if properly managed. The 2 tations, including those of TET2, ASXL1, EZH2 DNMT3, most important life-limiting complications of PV and ET IDH1/2, and TP53 [127]. are thrombohemorrhagic events and myelofibrosis/AML Clinical risk factors for LT include advanced age, transformation. Vascular events are at least in part pre- karyotypic abnormalities, prior therapy with alkylating ventable with counseling on risk factors, phlebotomy (for

380 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal Clinical Review

patients with PV), antiplatelet therapy, and cytoreduction 13. Wolanskyj AP, Schwager SM, et al. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, with hydroxyurea, IFNs, or anagrelide (for patients with and prognostic factors. Mayo Clin Proc 2006;81:159–66. ET). In addition, ruxolitinib was recently approved for PV 14. Srour SA, Devesa SS, Morton LM, et al. Incidence and patient sur- patients after hydroxyurea failure. PV/ET transformation vival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12. Br J Haematol in myelofibrosis or AML is part of the natural history of 2016;174:382–96. the disease and no therapy has been shown to prevent 15. Titmarsh GJ, Duncombe AS, McMullin MF, et al. How common are myeloproliferative neoplasms? A systematic review and meta-anal- it. Treatment follows recommendations set forth for PMF ysis. Am J Hematol 2014;89:581–7. and AML, but results are generally poorer and novel strat- 16. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, egies are needed to improve outcomes. essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 2014;92:289–97. 17. Stein BL, Gotlib J, Arcasoy M, et al. Historical views, conventional approaches, and evolving management strategies for myeloprolifer- Corresponding author: Lorenzo Falchi, MD, Columbia University ative neoplasms. J Natl Compr Canc Netw 2015;13:424–34. Medical Center, New York, NY. 18. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombo- Financial disclosures: None. cythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387–97. References 19. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the 1. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: 2005;365:1054–61. IARC; 2008. 20. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in 2. Alvarez-Larran A, Pereira A, Arellano-Rodrigo E, et al. Cytoreduction polycythemia vera and idiopathic erythrocytosis. N Engl J Med plus low-dose aspirin versus cytoreduction alone as primary pro- 2007;356:459–68. phylaxis of thrombosis in patients with high-risk essential thrombo- 21. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopatho- cythaemia: an observational study. Br J Haematol 2013;161:865–71. logic correlates of JAK2 exon 12 mutations in JAK2V617F-negative 3. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 polycythemia vera. Leukemia 2007;21:1960–3. update on diagnosis, risk-stratification, and management. Am J 22. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical Hematol 2013;88:507–16. features of the myeloproliferative neoplasm associated with JAK2 4. Michiels JJ, Berneman Z, Schroyens W, et al. Platelet-mediat- exon 12 mutations. Blood 2011;117:2813–6. ed erythromelalgic, cerebral, ocular and coronary microvascular 23. Abe M, Suzuki K, Inagaki O, et al. A novel MPL point muta- ischemic and thrombotic manifestations in patients with essential tion resulting in thrombopoietin-independent activation. Leukemia thrombocythemia and polycythemia vera: a distinct aspirin-re- 2002;16:1500–6. sponsive and coumadin-resistant arterial thrombophilia. Platelets 24. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic 2006;17:528–44. activating mutation in myelofibrosis with myeloid metaplasia. PLoS 5. James C, Ugo V, Couedic J-PL, et al. A unique clonal JAK2 mu- Med 2006;3:e270. tation leading to constitutive signalling causes polycythaemia vera. 25. Pardanani AD, Levine RL, Lasho T, et al. MPL515 mutations in Nature 2005;434:1144–8. myeloproliferative and other myeloid disorders: a study of 1182 6. Kralovics R, Passamonti F, Buser A, et al. A gain-of-function patients. Blood 2006;108:3472–6. mutation of JAK2 in myeloproliferative disorders.N Engl J Med 26. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in 2005;352:1779–90. myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 7. Verstovsek S, Mesa R, Gotlib J, et al. A double-blind, place- 2013;369:2391–405. bo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 27. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic muta- 2012;366:799–807. tions of calreticulin in myeloproliferative neoplasms. N Engl J Med 8. Harrison C, Kiladjian J, Al-Ali H, et al. JAK Inhibition with ruxoli- 2013;369:2379–90. tinib versus best available therapy for myelofibrosis.N Engl J Med 28. Wang WA, Groenendyk J, Michalak M. Calreticulin signaling in 2012;366:787–98. health and disease. Int J Biochem Cell Biol 2012;44:842–6. 9. Berglund S, Zettervall O. Incidence of polycythemia vera in a de- 29. Saeidi K. Myeloproliferative neoplasms: Current molecular biology fined population. Eur J Haematol 1992;48:20–6. and genetics. Crit Rev Oncol Hematol 2016;98:375–89. 10. Rozman C, Giralt M, Feliu E, et al. Life expectancy of patients 30. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the with chronic nonleukemic myeloproliferative disorders. Cancer World Health Organization classification of myeloid neoplasms and 1991;67:2658–63. acute leukemia. Blood 2016;127: 2391–405. 11. Passamonti F, Rumi E, Pungolino E, et al. Life expectancy and 31. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and prognostic factors for survival in patients with polycythemia vera quality of life in myeloproliferative disorders (MPDs): an international and essential thrombocythemia. Am J Med 2004;117:755–61. Internet-based survey of 1179 MPD patients. Cancer 2007;109: 12. Hultcrantz M, Kristinsson SY, Andersson TM, et al. Patterns of sur- 68–76. vival among patients with myeloproliferative neoplasms diagnosed 32. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in Sweden from 1973 to 2008: a population-based study. J Clin in a large cohort of patients with polycythemia vera. J Clin Oncol Oncol 2012;30:2995–3001. 2005;23:2224–32.

www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 381 Polycythemia Vera and Essential Thrombocythemia

33. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Hematology 2010;15: 187–92. Neoplasm Symptom Assessment Form (MPN-SAF): international 52. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of prospective validation and reliability trial in 402 patients. Blood homozygous JAK2 617V>F mutation in patients with polycythemia 2011;118:401–8. vera or essential thrombocythemia. Blood 2007;110:840–6. 34. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neo- 53. Carobbio A, Finazzi G, Antonioli E, et al. JAK2V617F allele burden plasm (MPN) symptom assessment form total symptom score: and thrombosis: a direct comparison in essential thrombocythemia prospective international assessment of an abbreviated symptom and polycythemia vera. Exp Hematol 2009;37:1016–21. burden scoring system among patients with MPNs. J Clin Oncol 54. Alvarez-Larran A, Bellosillo B, Pereira A, et al. JAK2V617F moni- 2012;30:4098–103. toring in polycythemia vera and essential thrombocythemia: clinical 35. Casini A, Fontana P, Lecompte TP. Thrombotic complications of usefulness for predicting myelofibrotic transformation and throm- myeloproliferative neoplasms: risk assessment and risk-guided botic events. Am J Hematol 2014;89:517–23. management. J Thromb Haemost 2013;11:1215–27. 55. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-rel- 36. Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and evant revision of IPSET-thrombosis based on 1019 patients thrombosis. Blood 2013;122:2176-–84. with WHO-defined essential thrombocythemia. Blood Cancer J 37. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and 2015;5:e369. venous haematocrit in primary myeloproliferative polychytemia. 56. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and Lancet 1978;2:1219–22. venous thrombosis in WHO-defined essential thrombocythemia: an 38. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major international study of 891 patients. Blood 2011;117:5857–9. thrombotic risk factor in patients with polycythemia vera. Blood 57. Alvarez-Larran A, Cervantes F, Bellosillo B, et al. Essential thrombo- 2007;109:2446–52. cythemia in young individuals: frequency and risk factors for vascu- 39. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among lar events and evolution to myelofibrosis in 126 patients. Leukemia 1545 patients with contemporary polycythemia vera: an internation- 2007;21:1218–23. al study. Leukemia 2013;27:1874–81. 58. Jantunen R, Juvonen E, Ikkala E, et al. The predictive value of 40. Barbui T, Falanga A. Molecular biomarkers of thrombosis in myelop- vascular risk factors and gender for the development of throm- roliferative neoplasms. Thromb Res 2016;140 Suppl 1:S71–75. botic complications in essential thrombocythemia. Ann Hematol 41. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of 2001;80:74–8. essential thrombocythaemia and relation to polycythaemia vera 59. Besses C, Cervantes F, Pereira A, et al. Major vascular complica- based on JAK2 V617F mutation status: a prospective study. Lancet tions in essential thrombocythemia: a study of the predictive factors 2005;366:1945–53. in a series of 148 patients. Leukemia 1999;13:150–4. 42. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term surviv- 60. Haider M, Gangat N, Hanson C, Tefferi A. Splenomegaly and throm- al and blast transformation in molecularly annotated essential bosis risk in essential thrombocythemia: the mayo clinic experience. thrombocythemia, polycythemia vera, and myelofibrosis. Blood Am J Hematol 2016;91: E296–297. 2014;124:2507–13. 61. Carobbio A, Finazzi G, Antonioli E, et al. Thrombocytosis and leu- 43. Qin Y, Wang X, Zhao C, et al. The impact of JAK2V617F mutation kocytosis interaction in vascular complications of essential throm- on different types of thrombosis risk in patients with essential thrombocythemia. Blood 2008;112:3135–7. bocythemia: a meta-analysis. Int J Hematol 2015;102:170–80. 62. Palandri F, Polverelli N, Catani L, et al. Impact of leukocytosis on 44. Ziakas PD. Effect of JAK2 V617F on thrombotic risk in patients with thrombotic risk and survival in 532 patients with essential thrombo- essential thrombocythemia: measuring the uncertain. Haematolog- cythemia: a retrospective study. Ann Hematol 2011;90:933–8. ica 2008;93:1412–4. 63. Campbell PJ, MacLean C, Beer PA, et al. Correlation of blood 45. Lussana F, Dentali F, Abbate R, et al. Screening for thrombophilia counts with vascular complications in essential thrombocythemia: and antithrombotic prophylaxis in pregnancy: Guidelines of the Ital- analysis of the prospective PT1 cohort. Blood 2012;120:1409–11. ian Society for Haemostasis and Thrombosis (SISET). Thromb Res 64. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients 2009;124: e19–25. with essential thrombocythemia and a high risk of thrombosis. N 46. Dahabreh IJ, Zoi K, Giannouli S, et al. Is JAK2 V617F mutation more Engl J Med 1995;332:1132–6. than a diagnostic index? A meta-analysis of clinical outcomes in 65. van Genderen PJ, Mulder PG, Waleboer M, et al. Prevention essential thrombocythemia. Leuk Res 2009;33:67–73. and treatment of thrombotic complications in essential throm- 47. Cho YU, Chi HS, Lee EH, et al. Comparison of clinicopathologic bocythaemia: efficacy and safety of aspirin. Br J Haematol findings according to JAK2 V617F mutation in patients with essen- 1997;97:179–84. tial thrombocythemia. Int J Hematol 2009;89:39–44. 66. Storen EC, Tefferi A. Long-term use of anagrelide in young patients 48. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in with essential thrombocythemia. Blood 2001;97:863–6. essential thrombocythaemia: clinical associations and long-term 67. De Stefano V, Za T, Rossi E, et al. Recurrent thrombosis in patients prognostic relevance. Br J Haematol 2005;131:208–13. with polycythemia vera and essential thrombocythemia: incidence, 49. Antonioli E, Guglielmelli P, Pancrazzi A, et al. Clinical implications of risk factors, and effect of treatments. Haematologica 2008;93: the JAK2 V617F mutation in essential thrombocythemia. Leukemia 372–80. 2005;19:1847–9. 68. Alvarez-Larran A, Cervantes F, Pereira A, et al. Observation versus 50. Palandri F, Catani L, Testoni N, et al. Long-term follow-up of 386 antiplatelet therapy as primary prophylaxis for thrombosis in low-risk consecutive patients with essential thrombocythemia: safety of essential thrombocythemia. Blood 2010;116:1205–10. cytoreductive therapy. Am J Hematol 2009;84:215–20. 69. Palandri F, Polverelli N, Catani L, et al. Bleeding in essential throm- 51. Chim CS, Sim JP, Chan CC, et al. Impact of JAK2V617F mutation bocythaemia: a retrospective analysis on 565 patients. Br J Haema- on thrombosis and myeloid transformation in essential thrombo- tol 2012;156:281–4. cythemia: a multivariate analysis by Cox regression in 141 patients. 70. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin

382 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal Clinical Review

mutations on clinical and hematological phenotype and outcome in 90. Kiladjian JJ, Chevret S, Dosquet C, et al. Treatment of polycythemia essential thrombocythemia. Blood 2014;123:1552–5. vera with hydroxyurea and pipobroman: final results of a random- 71. Tefferi A, Wassie EA, Lasho TL, et al. Calreticulin mutations ized trial initiated in 1980. J Clin Oncol 2011;29:3907–13. and long-term survival in essential thrombocythemia. Leukemia 91. Kaplan ME, Mack K, Goldberg JD, et al. Long-term management 2014;28:2300–3. of polycythemia vera with hydroxyurea: a progress report. Semin 72. Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status Hematol 1986;23:167–71. defines subtypes of essential thrombocythemia with substantially 92. Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: different clinical course and outcomes. Blood 2014;123:1544–51. a Polycythemia Vera Study group report on hydroxyurea in patients 73. Palandri F, Latagliata R, Polverelli N, et al. Mutations and long-term with polycythemia vera. Semin Hematol 1997;34:17–23. outcome of 217 young patients with essential thrombocythemia or 93. Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycy- early primary myelofibrosis. Leukemia 2015;29:1344–9. themia vera: an analysis of 1638 patients enrolled in a prospective 74. Fu R, Xuan M, Zhou Y, et al. Analysis of calreticulin mutations in Chi- observational study. Blood 2005;105: 2664–70. nese patients with essential thrombocythemia: clinical implications 94. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for in diagnosis, prognosis and treatment. Leukemia 2014;28:1912–4. polycythemia vera and essential thrombocythemia: an ELN and 75. Tefferi A, Wassie EA, Guglielmelli P, et al. Type 1 versus Type 2 IWG-MRT consensus project. Blood 2013;121:4778–81. calreticulin mutations in essential thrombocythemia: a collaborative 95. Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and study of 1027 patients. Am J Hematol 2014;89:E121–4. prognostic value of the European LeukemiaNet criteria for clinico- 76. Pietra D, Rumi E, Ferretti VV, et al. Differential clinical effects of hematologic response, resistance, and intolerance to hydroxyurea different mutation subtypes in CALR-mutant myeloproliferative neo- in polycythemia vera. Blood 2012;119:1363–9. plasms. Leukemia 2016;30: 431–8. 96. Stein BL, Tiu RV. Biological rationale and clinical use of interferon 77. Rumi E, Pietra D, Guglielmelli P, et al. Acquired copy-neutral loss of in the classical BCR-ABL-negative myeloproliferative neoplasms. J heterozygosity of chromosome 1p as a molecular event associated Interferon Cytokine Res 2013;33: 145–53. with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. 97. Ludwig H, Cortelezzi A, Van Camp BG, et al. Treatment with Blood 2013;121:4388–95. recombinant interferon-alpha-2C: multiple myeloma and thrombo- 78. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in my- cythaemia in myeloproliferative diseases. Oncology 1985;42 Suppl eloproliferative disorders: analysis of the PT-1 cohort. Blood 1:19–25. 2008;112:141–9. 98. Silver RT. Long-term effects of the treatment of polycythemia vera 79. Gangat N, Wassie EA, Lasho TL, et al. Mutations and thrombosis with recombinant interferon-alpha. Cancer 2006;107:451–8. in essential thrombocythemia: prognostic interaction with age and 99. Kiladjian JJ, Mesa RA, Hoffman R. The renaissance of interfer- thrombosis history. Eur J Haematol 2015;94:31–6. on therapy for the treatment of myeloid malignancies. Blood 80. Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis 2011;117:4706–15. in myeloproliferative neoplasms. Br J Haematol 2013;162:730–47. 100. Veronese FM, Mero A. The impact of PEGylation on biological ther- 81. Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease apies. BioDrugs 2008;22:315–29. characteristics and clinical outcomes in polycythemia vera. Leuk 101. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-al- Lymph 2013;54:1989–95. fa-2a induces complete hematologic and molecular responses with 82. Landolfi R, Di Gennaro L, Nicolazzi MA, et al. Polycythemia low toxicity in polycythemia vera. Blood 2008;112:3065–72. vera: gender-related phenotypic differences. Intern Emerg Med 102. Turlure P, Cambier N, Roussel M, et al. Complete hematologi- 2012;7:509–15. cal, molecular and histological remissions without cytoreductive 83. Winslow ER, Brunt LM, Drebin JA, et al. Portal vein thrombosis after treatment lasting after pegylated-interferon {alpha}-2a (peg-IFN{al- splenectomy. Am J Surg 2002;184:631–6. pha}-2a) therapy in polycythemia vera (PV): long term results of a 84. Smalberg JH, Arends LR, Valla DC, et al. Myeloproliferative neo- phase 2 trial [abstract]. Blood 2011;118(21). Abstract 280. plasms in Budd-Chiari syndrome and portal vein thrombosis: a 103. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated meta-analysis. Blood 2012;120:4921–8. interferon alfa-2a yields high rates of hematologic and molecular 85. Dentali F, Squizzato A, Brivio L, et al. JAK2V617F mutation for the response in patients with advanced essential thrombocythemia and early diagnosis of Ph- myeloproliferative neoplasms in patients polycythemia vera. J Clin Oncol 2009;27:5418–24. with venous thromboembolism: a meta-analysis. Blood 2009;113: 104. Quintas-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular 5617–23. analysis of patients with polycythemia vera or essential thrombo- 86. Pardanani A, Lasho TL, Hussein K, et al. JAK2V617F mutation cythemia receiving pegylated interferon a-2a. Blood 2013;122: screening as part of the hypercoagulable work-up in the absence of 893–901. splanchnic venous thrombosis or overt myeloproliferative neoplasm: 105. Samuelsson J, Hasselbalch H, Bruserud O, et al. A phase II trial of assessment of value in a series of 664 consecutive patients. Mayo pegylated interferon alpha-2b therapy for polycythemia vera and Clin Proc 2008;83:457–9. essential thrombocythemia: feasibility, clinical and biologic effects, 87. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative clas- and impact on quality of life. Cancer 2006;106:2397–405. sical myeloproliferative neoplasms: critical concepts and manage- 106. Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy ment recommendations from European LeukemiaNet. J Clin Oncol in BCR-ABL-negative myeloproliferative disorders: final result of a 2011;29:761–70. phase 2 study. Cancer 2007; 110:2012–18. 88. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose 107. Them NC, Bagienski K, Berg T, et al. Molecular responses and aspirin in polycythemia vera. N Engl J Med 2004;350:114–24. chromosomal aberrations in patients with polycythemia vera treat- 89. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events ed with peg-proline-interferon alpha-2b. Am J Hematol 2015;90: and intensity of treatment in polycythemia vera. N Engl J Med 288–94. 2013;368:22–33. 108. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-

www.mdedge.com/jcomjournal Vol. 25, No. 8 October 2018 JCOM 383 Polycythemia Vera and Essential Thrombocythemia

PV a randomized controlled phase 3 trial comparing ropeginterferon available therapy for ET intolerant or resistant to hydroxycarbam- alfa-2b to hydroxyurea in polycythemia vera patients [abstract]. ide in a randomized trial. Blood 2017 Aug 9. pii: blood-2017-05- Blood 2016;128(suppl 22). Abstract 475. 785790 . 109. van Genderen PJ, van Vliet HH, Prins FJ, et al. Excessive prolon- 123. Bose P, Verstovsek S. Drug development pipeline for myeloprolifer- gation of the bleeding time by aspirin in essential thrombocythemia ative neoplasms: potential future impact on guidelines and manage- is related to a decrease of large von Willebrand factor multimers in ment. J Natl Compr Canc Netw 2016;14:1613–24. plasma. Ann Hematol 1997;75:215–20. 124. Cerquozzi S, Teffieri A. Blast transformation and fibrotic progression 110. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients in polycythemia vera and essential thrombocythemia: a literature with essential thrombocythemia and a high risk of thrombosis. N review of incidence and risk factors. Blood Cancer J 2015;Nov Engl J Med 1995;332:1132–7. 13;5:e366. 111. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared 125. Passamonti F, Rumi E, Caramella M, et al. A dynamic prognostic with anagrelide in high-risk essential thrombocythemia. N Engl J model to predict survival in post-polycythemia vera myelofibrosis. Med 2005;353:33–45. Blood 2008;111:3383–7. 112. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared 126. Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis with hydroxyurea in WHO-classified essential thrombocythemia: (PMF), post polycythemia vera myelofibrosis (post- PV MF), post the ANAHYDRET Study, a randomized controlled trial. Blood essential thrombocythemia myelofibrosis (post-ET MF), blast phase 2013;121:1720–8. PMF (PMF-BP): Consensus on terminology by the international 113. Alvarado Y, Cortes J, Verstovsek S, et al. Pilot study of pegylated working group for myelofibrosis research and treatment (IWG-MRT). interferon-alpha 2b in patients with essential thrombocythemia. Leuk Res 2007;31:737–40. Cancer Chemother Pharmacol 2003;51:81–6. 127. Rampal R, Mascarenhas J. Pathogenesis and management of 114. Barosi G, Tefferi A, Barbui T, ad hoc committee ‘Definition of acute myeloid leukemia that has evolved from a myeloproliferative clinically relevant outcomes for contemporarily clinical trials in Ph- neoplasm. Curr Opin Hematol 2014;21:65–71. neg M. Do current response criteria in classical Ph-negative my- 128. Chihara D, Kantarjian HM, Newberry KJ, et al. Survival outcome of eloproliferative neoplasms capture benefit for patients? Leukemia patients with acute myeloid leukemia transformed from myeloprolif- 2012;26:1148–9. erative neoplasms [abstract]. Blood 2016;128. Abstract 1940. 115. Bjorkholm M, Derolf AR, Hultcrantz M, et al. Treatment-related risk 129. Tam CS, Nussenzveig RM, Popat U, et al. The natural history and factors for transformation to acute myeloid leukemia and myelo- treatment outcome of blast phase BCR-ABL-myeloproliferative dysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol neoplasms. Blood 2008;112:1628–37. 2011;29:2410–5. 130. Kundranda MN, Tibes R, Mesa RA. Transformation of a chronic 116. Alvarez-Larran A, Martinez-Aviles L, Hernandez-Boluda JC, et al. myeloproliferative neoplasm to acute myelogenous leukemia: does Busulfan in patients with polycythemia vera or essential throm- anything work? Curr Hematol Malig Rep 2012;7:78–86. bocythemia refractory or intolerant to hydroxyurea. Ann Hematol 131. Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of 2014;93:2037–43. decitabine, a hypomethylating agent, in patients with high-risk pri- 117. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study mary myelofibrosis and myeloproliferative neoplasm in accelerated of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with or blastic/acute myeloid leukemia phase. Leuk Res 2015;39:950–6. advanced polycythemia vera who are refractory or intolerant to 132. Thepot S, Itzykson R, Seegers V, et al. Treatment of progression hydroxyurea. Cancer 2014;120: 513–20. of Philadelphia-negative myeloproliferative neoplasms to myelo- 118. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib in dysplastic syndrome or acute myeloid leukemia by azacitidine: a polycythemia vera resistant to or intolerant of hydroxyurea. N Engl J report on 54 cases on the behalf of the Groupe Francophone des Med 2015; 372:426–35. Myelodysplasies (GFM). Blood 2010;116:3735–42. 119. Verstovsek S, Vannucchi AM, Griesshammer M, et al. Ruxolitinib 133. Pemmaraju N, Kantarjian H, Kadia T, et al. A phase I/II study of versus best available therapy in patients with polycythemia vera: the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with 80-week follow-up from the RESPONSE trial. Haematologica relapsed or refractory acute myeloid leukemia. Clin Lymphoma 2016;101:821–9. Myeloma Leuk 2015;15:171–6. 120. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the 134. Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and treatment of inadequately controlled polycythaemia vera without efficacy of combined ruxolitinib and decitabine in patients with splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b blast-phase MPN and post-MPN AML: results of a phase I study study. Lancet Oncol 2017;18:88–99. (Myeloproliferative Disorders Research Consortium 109 trial) [ab- 121. Verstovsek S, Passamonti F, Rambaldi A, et al. Long-term results stract]. Blood 2016;128. Abstract 1124. from a phase II open-label study of ruxolitinib in patients with es- 135. Bose P, Verstovsek S, Gasior Y, et al. Phase I/II study of ruxolitinib sential thrombocythemia refractory to or intolerant of hydroxyurea (RUX) with decitabine (DAC) in patients with post-myeloproliferative [abstract]. Blood 2014;124. Abstract 1847. neoplasm acute myeloid leukemia (post-MPN AML): phase I results 122. Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib versus best [abstract]. Blood 2016;128. Abstract 4262.

384 JCOM October 2018 Vol. 25, No. 8 www.mdedge.com/jcomjournal